tbuckley/cabot-search huggingface dataset:
Abstract 3325: ERK inhibitor increases cancer stem cell population in NSCLC through Slug-Mediated epithelial-to-mesenchymal transition
Authors: Shurui Cai, Na Li, Xuetao Bai, Ananya Banerjee, Lavudi Kousalya, Qi-en Wang
Journal: Cancer Research (2022)

Abstract The aberrant activation of the Mitogen-activated protein kinase pathway (MAPK/ERK pathway) has been found to play an important role in many cancers including non-small-cell lung cancer (NSCLC). Multiple inhibitors targeting this pathway have been developed to treat cancer patients harboring the aberrant MAPK pathway genes. ERK inhibitors (ERKi) have been shown to be effective in a variety of solid-tumor malignancies, but like other MAPK inhibitors, they rarely confer complete and durable responses. Therefore, it is important to define the mechanism underlying potential tumor relapse following ERKi treatment. In this study, we found that ERKi treatment expanded the cancer stem cell (CSC) population in various NSCLC cell lines and a NSCLC patient-derived xenograft (PDX) harboring aberrant MAPK signaling. Such expansion of the CSC population is mainly caused by enhanced epithelial-to-mesenchymal transition (EMT)-mediated cancer cell dedifferentiation. Mechanistically, we revealed that ERK inhibition induces EMT via pSTAT3-mediated upregulation of EMT-transcription factor Slug. Specifically, we found that ERK inhibition increased phosphorylation of STAT3 at Y705, which further increased the expression of miR-204. Increased miR-204 then downregulated expression of SPDEF, a transcriptional repressor of Slug, thereby derepressing Slug expression. Moreover, we found that a low expression of Slug is necessary for maintaining stemness properties of CSCs. Thus, ERKi treatment-increased Slug must be downregulated to allow these cells to fully acquire stemness, and this process is mediated by a Slug-miR-200c negative feedback loop. Finally, we demonstrated that the JAK/STAT pathway inhibitor Ruxolitinib can block the ERK inhibitor-induced EMT and CSCs expansion, providing a feasible combination inhibitor approach for treating NSCLC patients. Overall, these studies provide a better understanding of the tumor relapse following ERKi treatment, and define the role of Slug in de novo production of CSCs and their maintenance. Citation Format: Shurui Cai, Na Li, Xuetao Bai, Ananya Banerjee, Lavudi Kousalya, Qi-en Wang. ERK inhibitor increases cancer stem cell population in NSCLC through Slug-Mediated epithelial-to-mesenchymal transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3325.
Abstract 3386: Detection of TGFbR2 frameshift mutation
Authors: Henrik K. Eriksen, Jon A. Eriksen
Journal: Cancer Research (2022)

Abstract TGFβR2 a10→a9 frameshift mutation is an early occurring cancer driver mutation and mutant TGFβR2 cell free DNA (cfDNA) is therefore a potential biomarker for early detection of cancer (E.G. Lynch Syndrome) as well as for monitoring response to cancer treatment. The frameshift mutation is associated with micro satellite instability (MSI) and is found in 80% of MSI-colorectal cancers (MSI-CRC) and in over 90% of hereditary nonpolyposis colorectal cancer. Here we show that cell free mutant (a9) TGFβR2 DNA is present in liquid biopsies from MSI-CRC patients and that the a9 micro satellite of mutant TGFβR2 can be selectively detected by using specially designed PCR primers modelled after the a9 microsatellite. PCR and primers defining a fragment of TGFβR2 comprising the a10/a9 microsatellite was used to amplify cfDNA extracted from MSI-CRC and microsatellite stable-CRC (MSS-CRC) patients. The resulting PCR products were analysed and confirmed by DNA sequencing after gel electrophoresis. In addition, primers modelled after the shorter a9 microsatellite was designed and tested using synthetic DNA of both TGFβR2 variants. Despite the naturally established mismatch between the a10 sequence and primers modelled after the a9 sequence, conventionally designed primers could not differentiate enough for specific annealing to the a9 sequence. A further mismatch with the a10 sequence was introduced at the 3’ end of the primer, which, in combination with the already established mismatch, denied the primer tail-end annellation with the a10 sequence that is necessary for polymerase amplification of this sequence. Experiments to optimise PCR conditions and buffer solution were conducted prior to analysing the cfDNA extracted from the patient samples. It was found that TGFβR2 DNA was present in cfDNA from all (10/10) CRC patients tested and that TGFβR2 a10→a9 frameshift was present in all (5/5) MSI-CRC patients and none (0/5) of MSS-CRC patients tested, shown by sequencing. PCR using the selected a9 modelled primer yielded a PCR product that was clearly detectable on the electrophoresis gel only for cfDNA from the MSI-CRC patients (5/5). The results show that TGFβR2 a10→a9 frameshift DNA is present in cfDNA of liquid biopsies from MSI-CRC patients which establishes cell free TFGβR2 frameshift DNA as a potential biomarker for early detection of hereditary CRC (Lynch Syndrome) as well as for monitoring cancer progression and remission of sporadic MSI-CRC. Citation Format: Henrik K. Eriksen, Jon A. Eriksen. Detection of TGFbR2 frameshift mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3386.
Diversity within the neurosurgical oncology workforce in the United States: A cross-sectional study with proposed strategies to pave the path forward
Authors: Zerubabbel Ketema Asfaw, Analiz Rodriguez, Tiffany Renee Hodges, Madhu Mazumdar, Serena Zhan, Michael Lim, Isabelle Margherita Germano
Journal: Neuro-Oncology (2022)

Abstract Background Improving and fostering diversity within the neurosurgical workforce has become a high priority. This cross-sectional study aims to provide data on the diversity of neurosurgical oncology faculty (NSOF) in the US. Methods All 115 neurosurgery (NS) Accreditation Council for Graduate Medical Education (ACGME) accredited programs were included in this study. The academic rank, academic and clinical title(s), gender, race, and hiring date of neurosurgical faculty with a primary focus on neurosurgical oncology (NSOF) were recorded. Geographical distribution and “top 10” programs were tabulated according to published data. Underrepresented minorities in medicine (URiM) faculty were identified according to the AAMC definition. Results The NSOF workforce constitutes 21% of the total NS faculty. Of these, 10.1% are women and 9.9% are URiM (P &amp;lt; .001). Currently, 58% of neurosurgery programs (NSP) do not have URiM and/or women NSOF. The top 10 ranked NSP, according to Blue Ridge Institute for Medical Research, had a significantly less URiM NSOF (P = .019) than nontop 10 ranked programs. There was a decreasing trend in the proportion of URiM at higher academic ranks (P = .019). All of the URiM department chairs (3/113)—all men—and 1/3 women department chairs nationwide subspecialized in neurosurgical oncology. Conclusions Neurosurgical oncology is a sought-after subspecialty attracting a fifth of neurosurgeons practicing in ACGME-accredited training programs. Changing demographics and the benefits of workforce diversity represent a great opportunity for our field to continue leading inclusion efforts and attracting the best and brightest.
Abstract 413: WT RAS signaling is an essential therapeutic target in RAS mutated cancers
Authors: Nancy E. Sealover, Robert L. Kortum
Journal: Cancer Research (2022)

Abstract Single-agent targeting of RAS-mutated cancers using RAF/MEK/ERK or PI3K/AKT pathway inhibitors is ineffective; blocking one pathway relieves negative feedback control of RTK signaling and hyperactivates parallel effector pathways. While combined MEK and PI3K inhibition is effective in preclinical models, toxicity of this combination prevents its clinical use. Alternative strategies for treating RAS-mutated cancers are essential. Therapeutics directly targeting mutated RAS proteins have the potential to spare normal cellular function thereby lessening overall toxicity. Unfortunately, direct RAS inhibition as a monotherapy does not fully block RAS effector signaling. RAS proteins show differential activation of RAF and PI3K pathways: KRAS potently activates RAF but poorly activates PI3K, whereas HRAS potently activates PI3K but poorly activates RAF. Further, mutant RAS inhibition relieves negative feedback controls leading to rapid hyperactivation of RTK−WT RAS signaling. A more comprehensive understanding of the interplay between mutant RAS and RTK−WT RAS signaling is essential to developing rational therapeutic approaches to treat RAS-mutated cancers. We found that WT RAS enhanced mutant RAS-driven transformation by activating RAS effectors poorly engaged by mutated RAS. Further, inhibition of RAS effectors activated poorly by mutant RAS synergized with and limited resistance to mutant HRAS and KRAS inhibitors. The mutant HRAS inhibitor tipifarnib blocked PI3K signaling and synergized with MEK inhibitors in HRAS-mutated cancer cell lines; covalent KRASG12C inhibitors blocked MEK signaling and synergized with PI3K inhibitors in KRASG12C-mutated cell lines. Synergy between inhibitors of mutant RAS and RAS effectors was dependent on intact RTK/WT RAS signaling and was lost in both RASless or SOSless MEFs. Upstream of RAS, the RASGEFs SOS1 and SOS2 showed unique and overlapping functions to promote mutant RAS-driven transformation. SOS1 was critical for mutant RAS (G12V) activation and SOS1 inhibition augmented the efficacy of mutant RAS inhibitors. RTK−SOS2−PI3K signaling protected cells from anoikis and mediated mutant KRAS-driven transformation. These results should inform the design of clinical trials for patients with RAS-mutated cancers. Citation Format: Nancy E. Sealover, Robert L. Kortum. WT RAS signaling is an essential therapeutic target in RAS mutated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 413.
Abstract 1283: Single intra-tumoral injection of gaseous nitric oxide induces an adaptive immune response in a mouse CT-26 solid tumor model
Authors: Hila Confino, Matan Goldshtein, Yakir Levi, Lidor Malka, Amir Avniel, Steve Lisi, Ido Wolf
Journal: Cancer Research (2022)

Abstract Background: Metastases are responsible for a significant portion of the morbidity and mortality in cancer patients. In situ destruction of tumor mass has been reported to provide the immune system with an antigen source for the induction of antitumor immunity, which can then attack distant metastases. Nitric oxide (NO) acts as a signaling molecule in multiple disease states, including cancer. NO has been shown to activate innate and adaptive responses of the immune system against tumors. In a previous Beyond Air study, 89% of CT26 tumor bearing mice treated with 50,000 parts per million (ppm) gaseous NO (gNO), rejected a secondary tumor induction. Here, we assessed the effects of a single intra-tumoral injection of gNO at concentrations of 20,000-50,000 ppm on immune cell recruitment in the tumor, spleen, and blood. Methods: Mouse colon carcinoma (CT26) tumor bearing Balb/c mice underwent a single intra-tumoral treatment with 20,000 (n=3) or 50,000 (n=4) ppm gNO for 5 minutes. Mice treated with N2 (n=3), under the same conditions, served as a control. Tumors were removed 14 days post treatment and were histologically analyzed to test for immune cell penetration, inflammation, and necrosis. Immune cells from the spleen and blood were harvested 21 days post treatment and assessed via flow cytometry. Results: 1. Treatment with 50,000 ppm gNO resulted in higher levels of inflammation, lymphocytes and T-cell infiltration, and necrosis within the tumor compared to both N2 and 20,000 ppm NO, as viewed histologically. 2. Flow cytometry analysis of immune cells from the spleen revealed a 1.3-fold increase of both B cells and IFN-γ expressing T cells with 50,000 NO treatment, and a 1.3-fold increase of B cells and 1.1-fold increase of IFN-γ expressing T cells with 20,000 NO treatment, compared to N2. 3. A 29% reduction of myeloid-derived suppressor cells (MDSCs) was detected in spleens of mice treated with 50,000 ppm gNO, and 40% for 20,000 ppm, compared to mice treated with N2. Conclusion: Intra-tumoral injection of ultra-high doses of NO at 20,000 and 50,000 ppm gNO led to an increased recruitment and concentration of T and B cells. Additionally, 50,000 ppm NO led to an increase of lymphocyte infiltration to the tumor. Taken together, the data suggest that the increase in lymphocyte infiltration, B and T cell population, and the reduction of MDSCs, are indicative of an adaptive immune response that results in rejection of secondary tumors in gNO-treated mice. Citation Format: Hila Confino, Matan Goldshtein, Yakir Levi, Lidor Malka, Amir Avniel, Steve Lisi, Ido Wolf. Single intra-tumoral injection of gaseous nitric oxide induces an adaptive immune response in a mouse CT-26 solid tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1283.
The Multicenter Cancer of Pancreas Screening Study: Impact on Stage and Survival
Authors: Mohamad Dbouk, Bryson W. Katona, Randall E. Brand, Amitabh Chak, Sapna Syngal, James J. Farrell, Fay Kastrinos, Elena M. Stoffel, Amanda L. Blackford, Anil K. Rustgi, Beth Dudley, Linda S. Lee, Ankit Chhoda, Richard Kwon, Gregory G. Ginsberg, Alison P. Klein, Ihab Kamel, Ralph H. Hruban, Jin He, Eun Ji Shin, Anne Marie Lennon, Marcia Irene Canto, Michael Goggins
Journal: Journal of Clinical Oncology (2022)

To report pancreas surveillance outcomes of high-risk individuals within the multicenter Cancer of Pancreas Screening-5 (CAPS5) study and to update outcomes of patients enrolled in prior CAPS studies.
Abstract 5791: Microfluidics-based library preparation strategies for targeted high-throughput sequencing and RNA sequencing in hematological malignancies in clinical samples
Authors: Cédric Pastoret, Amyra Aliouat, Marie-Laure Boulland, Florent Denoual, Anne Desmares, Marie De Tayrac, Thierry Fest, Celeste Letellier
Journal: Cancer Research (2022)

Abstract Introduction We developed a unique panel of 54 target genes dedicated to hematological malignancies (HematoPanel) and screened 1,108 clinical samples. We also performed transcriptomic analysis and evaluated its relevance for patients with acute lymphoblastic leukemia (ALL). Methods DNA and RNA were extracted from cell pellets with the Maxwell® RSC (Promega®). Libraries for targeted high-throughput DNA sequencing (HTS) were generated in duplicate from 100 ng with the Advanta™ NGS Library Prep Assay kit using the LP 48.48 IFC (integrated fluidic circuit) on a Juno™ and sequenced on the NextSeq™ 550 (Illumina®) to a median depth of coverage of approximately 1,200X per sample. Transcriptomic libraries were generated from 50 ng RNA with the Advanta RNA-Seq XT NGS Library Prep Kit using the LP 48.Atlas™ IFC on Juno and sequenced on the NextSeq 550. A bioinformatics pipeline was developed for fusion transcript detection. Differential gene expression was analyzed with the DESeq2 package after STAR alignment. Results In 2020 we sequenced 1,108 consecutive samples in routine practice with HematoPanel. The main indications were the suspicion of myeloproliferative neoplasms (32%), the evaluation of chronic lymphocytic leukemia (23%), and the diagnostic workup of cytopenias (15%). We detected 1,306 mutations in 654 patients (59%) (1 to 8 mutations per sample). Eight genes (TET2, SF3B1, TP53, DNMT3A, ASXL1, JAK2, SRSF2 and MYD88) were reported as mutated for more than 50 patients. We sequenced 22 samples including the MOLT-4 cell line, healthy donor samples, and 16 ALL samples for transcriptomic evaluation. From ALL samples, we detected 5 fusion transcripts previously identified by specific PCR (1 BCR-ABL, 2 ETV6-RUNX1, 1 KMT2A-AFF1, 1 TCF3-PBX1). Moreover, we detected 4 other fusion transcripts for 3 patients (EBF1-PDGFRB, FGFR1-MYO18A, P2RY8-CRLF2, and PAX5-NOL4L). Interestingly, these patients clustered with the BCR-ABL positive sample based on their expression profile. It confirms the diagnosis of Phi-like ALL and thus offers a therapeutic target for these patients. Conclusion Microfluidics-based library prep using Juno offers a cost-effective strategy and straightforward workflows for both targeted HTS and RNA sequencing. We validated its use for hematological malignancy evaluation in routine practice. Citation Format: Cédric Pastoret, Amyra Aliouat, Marie-Laure Boulland, Florent Denoual, Anne Desmares, Marie De Tayrac, Thierry Fest, Celeste Letellier. Microfluidics-based library preparation strategies for targeted high-throughput sequencing and RNA sequencing in hematological malignancies in clinical samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5791.
Abstract 5992: Clonal evolutionary molecular mechanism of lymphatic metastasis in lung cancer
Authors: Nanan Guo, Hongmei Zhao
Journal: Cancer Research (2022)

Abstract Background: Lung cancer approximately accounts for more than a third of cancers, approximately 787,000 in China annually, which the death rate is greatest and most lethal in all cancers. However, clonal evolutionary molecular mechanism of lymphatic metastasis in lung cancer remains largely unknown according to previously reported. Methods: In this study, we systematically analyzed clonal evolution of 21 primary patients paired with lymphatic metastasis based on 500 gene-panel target sequencing and clinical characters. The two pipelines were performed to identify the subclones between primary and lymphatic metastasis on each patient, one is Pyclone, citup and Timespace, another is sciClone and clonevol. Furthermore, the genes associated with clonal evolutions were verified to be differentially mutated genes between primary and lymphatic metastasis in MSK-IMPACT 2017 cohort by fisher-test (P &amp;lt; 0.05). Results: The clonal clusters were explored in 3 of 21 patients (P08, P52, P57) with lung cancer by first pipeline, and 4 (P02, P08, P14 and P84) by second pipeline. The 2 genes TET2 and BRCA2 were identified to be associated with lymphatic metastasis. The mutation frequency of TET2 and BRCA2 were 4.2% and 7.1% in patients with lymphatic metastasis in validation cohort. Conclusions: We described molecular features of lung cancer patients with lymphatic metastasis. TET2 and BRCA2 mutations promoted development and evolution of tumor cells, which were insightful for developing novel therapeutic strategies to inhibit the progress of tumors. Keywords: Clonal Evolutionary, Molecular Mechanism, Lymphatic Metastasis, Lung cancer Citation Format: Nanan Guo, Hongmei Zhao. Clonal evolutionary molecular mechanism of lymphatic metastasis in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5992.
Abstract 5673: The role of NMDA receptors subunits in the progression of inflammatory breast cancer (IBC)
Authors: Laura L. Mendez Santacruz, Xavier S. Bittman-Soto, Keishla M. Rodriguez-Martir, Jesus M. Padilla Escalona, Esther Peterson, Carmen Maldonado-Vlaar
Journal: Cancer Research (2022)

Abstract Inflammatory Breast Cancer (IBC) has a 73% incidence of metastasis to the brain as compared to other cancer types like breast, lung, and bone cancer. Previous research showed that tumor cells from different breast cancer subtypes (-HR/-HER2) and (-HR/+ HER2) have a high incidence of crossing the blood-brain barrier and inducing increased expression of glutamate receptors NMDA subunits (NMDAR1 and NMDR2) in the brain. IBC is the most aggressive and rare type of breast cancer. The absence of a solid tumor is replaced by swelling, redness, and skin changes, resulting in many cases in misdiagnosis of an infection in the invasion and migration phase; this type of cancer blocks blood and lymphatic vessels in the breast's skin, causing local inflammation and rapid metastasis. However, little is known of the role that these glutamatergic receptors have in the development and/or progression of IBC. The present work provides a new understanding of the cellular and molecular effects NMDA receptors (NMDAR) have on oncogenic phenotypes in IBC. The detection and quantification of the NMDAR were evaluated by RT-qPCR, Western blot, and immunofluorescence (IF) techniques in deferments breast cancer cell lines (MCF7, MDA-MB-231) and IBC cell lines (SUM149, and SUM190). Also, NMDAR antagonists (memantine and dizocilpine "MK-801") were used in 2D and 3D cell cultures to see the pro-oncogenic effects of migration and proliferation in cell models. In addition to this, the autocrine regulation of Glutamate in IBC cell lines is verified. Results showed a significant increase in the expression of NMDARs in IBC cell lines. In the functional cell culture assays with NMDAR antagonists, a decrease in migration and proliferation in IBC cell lines was found. These findings may be related to the high aggressiveness and the high rate of metastasis by IBC within the brain. Our results have high clinical relevance since having extensive knowledge of the role of NMDARs in IBC progression could complement therapeutic approaches for patients with IBC. Citation Format: Laura L. Mendez Santacruz, Xavier S. Bittman-Soto, Keishla M. Rodriguez-Martir, Jesus M. Padilla Escalona, Esther Peterson, Carmen Maldonado-Vlaar. The role of NMDA receptors subunits in the progression of inflammatory breast cancer (IBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5673.